The main objective of this proposal is to apply recent progress in the serological and genetic definition of the DL-A antigen(s) in a closely-bred colony of dogs to the induction of immunological unresponsiveness to organ transplants in the canine species. Studies in progress at this time indicate that recipients exposed to supralethal total body irradiation, followed by a bone marrow transplant with cells obtained from a prospectively selected donor of known DL-A genotype may be rendered tolerant to kidney and skin allografts obtained from that donor. None of the recipients studied thus far has developed graft-versus-host disease. The immediate objective of this project is to assess the value of bone marrow transplantation for the induction of long-term survival of allografts of other organs, including kidney, skin, heart and liver. The immunological specificity of the induced tolerance will be investigated, and an attempt will be made to study the humoral and cellular mechanisms implicated in this type of allogeneic unresponsiveness. Studies under conditions of donor-recipient genotypic DL-A identity will provide the baseline for attempts to overcome minor and major DL-A incompatibility barriers, in a search for methods designed to permit the survival of bone marrow allografts from DL-A incompatible donors without the development of graft-versus-host disease in the recipients. Experience gained in the course of such studies will be extended to similar experiments in mongrel dogs.